Tumor extracellular matrix enhances invasive gene expression of breast cancer cells in 3D patient-derived scaffolds

Extracellular matrix (ECM) remodeling in cancer provides an essential substructure for tumor progression. We utilized patient-derived scaffolds (PDS) to model tumor ECM changes and study their impact on cell behavior. PDS were obtained from breast tumor and normal healthy breast tissue by decellularizing surgically resected specimens. We used PDS to design a 3D culture of the breast cancer cell line MCF-7. We utilized bioinformatics pipeline to identify hub genes indicative of cell invasiveness, and assessed their expression using quantitative real-time PCR. Our decellularization protocol led to decellularization of tissues while preserving key ECM components. ECM components such as collagen, glycosaminoglycans, collagen IV, and vimentin were significantly overexpressed in tumor compared to normal PDS. In 3D cultures, cells cultured on normal PDS had significantly lower viability and proliferation. Moreover, cells cultured for 15 days on tumor PDS showed significant overexpression of hub genes, CAV1, CXCR4, CNN3, MYB, and TGFB1, and secreted higher levels of IL-6 (122.91 vs. 30.23 pg/10⁶ cells, P < 0.05), all markers of an aggressive breast cancer phenotype. Breast cancer cells fail to acquire aggressive features when cultured in an ECM lacking tumor-specific alterations. This underscores the potential of therapeutic approaches targeting the mechanobiological properties of the tumor ECM.